Abstract
The systematic identification of genetic events driving cellular transformation and tumor progression in the absence of a highly recurrent oncogenic driver mutation is a challenge in cutaneous oncology. In cutaneous squamous cell carcinoma (cuSCC), the high UV-induced mutational burden poses a hurdle to achieve a complete molecular landscape of this disease. Here, we utilized the Sleeping Beauty transposon mutagenesis system to statistically define drivers of keratinocyte transformation and cuSCC progression in vivo in the absence of UV-IR, and identified both known tumor suppressor genes and novel oncogenic drivers of cuSCC. Functional analysis confirms an oncogenic role for the ZMIZ genes, and tumor suppressive roles for KMT2C, CREBBP and NCOA2, in the initiation or progression of human cuSCC. Taken together, our in vivo screen demonstrates an extremely heterogeneous genetic landscape of cuSCC initiation and progression, which can be harnessed to better understand skin oncogenic etiology and prioritize therapeutic candidates.
Highlights
Cutaneous squamous cell carcinoma is the second most common cancer in man, with approximately one million cases diagnosed annually in the United States
While most cutaneous squamous cell carcinoma (cuSCC) are highly treatable, more than twice as many individuals die from this disease as from melanoma
We describe a genetic screen in mice using a DNA transposon system to mutagenize the genome of keratinocytes and drive squamous cell carcinoma in the absence of UV
Summary
Cutaneous squamous cell carcinoma (cuSCC) is the second most common cancer in man, with approximately one million cases diagnosed annually in the United States. The majority of cuSCC are considered a low-risk neoplasm, up to 5% of high-risk cuSCCs are locally or distantly invasive and carry a poor prognosis due to a lack of biomarkers, therapeutic targets, or FDA-approved molecularly targeted therapies This represents a substantial unmet need for approximately 50,000 patients per year with high-risk cuSCC, and an opportunity to identify new therapeutic modalities that could improve disease outcomes. Using human cancer sequencing data alone, with some of the highest mutational burdens of any cancer, poses challenges to identify cooperating, low-penetrant mutations that lead to cancer progression This presents a need to develop in vivo model systems to help identify and prioritize novel cooperating candidate cancer drivers for keratinocyte transformation and subsequent progression to invasive cuSCC
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